Progressive nervous system deterioration is the major clinical consequence of human lysosomal storage diseases. The pathogenic basis for cell dysfunction and death due to lysosomal hypertrophy remains unknown. Unfortunately, only limited siccess has been achieved in preventing these diseases and effective therapy is not available. Combined ethical and scientific limitations inherent in patient trials make it imperative that research be performed with in vitro cell culture and animal model systems if progress in this important area of research is to continue. Feline Gm1 and Gm2 gangliosidoses have been thoroughly characterized and represent valuable models or research on human lysosomal storage diseases. Broad aims of this project involve utilization of the feline gangliosidoses to (1) elucidate pathogenic mechanisms of neuronal dysfunction and death in lysosomal diseases, and (2) continue development and assessment of therapeutic intervention in these diseases by methods having high potential for clinical application. Our recent studies of pathogenetic mechanisms in the gangliosidoses have resulted in evolution of a hypothesis that alterations in neuronal surface membrane production and regulation is a key element underlying neuronal dysfunction. Research proposed will extend current investigations of morphological and functional alterations of neurons and their transmitter systems. Advancements made through this provide a conceptual and methodological foundation for refinement and functional assessment of enzyme replacement therapy. Studies proposed will utilize complementary cell culture and in vivo methods to address fundamental questions concerning the correction of defective ganglioside (and other substrates) catabolism in neurons and other cells treated with exogenous lysosomal hydrolases.